ASH 2017 | Physically fit CLL patients show high response rates with obinutuzumab/ibrutinib combo in phase II Icll-07 Filo study

On Sunday 10 December 2017 during an oral abstract session at the 59^th Annual meeting American Society of Hematology (ASH), Anne-Sophie Michallet of Centre Léon Bérard in Lyon, France on behalf of her colleagues, presented results of a phase II, multi-center clinical trial in treatment-naïve, symptomatic, and medically-fit chronic lymphocytic leukemia (CLL) patients.

This abstract (#497), “Phase II, Multicenter Trial, Exploring “Chemo-Sparing” Strategy Associating Obinutuzumab+Ibrutinib Followed By a MRD Driven Strategy, in Previously Untreated Symptomatic Medically Fit Chronic Lymphocytic Leukemia Patients (CLL): Preliminary Results of the Induction Phase of the Icll-07 Filo Study,” was presented during Oral Session: 642. “CLL: Therapy, excluding Transplantation: Targeting MRD Negative CLL with Combinations of Novel Agents and Chemoimmunotherapy Regimens, New Treatments”; this summary is based on data presented at the live session and may supersede data included in the pre-published ASH abstract.

Highlight

• Combination of obinutuzumab and ibrutinib in previously untreated, fit CLL patients resulted in a high response rate with ORR and CR of 100% and 38%, respectively, in addition to tolerable toxicity

Treatment

• Physically fit, treatment-naïve patients with active Binet stage A to C CLL and no TP53 mutation/deletion were eligible if CIRS score was < 7 and ECOG 0 or 1
• Induction treatment: 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6), in combination with ibrutinib 420 mg daily for 9 months
  • First assessment of response was performed at 9 months, including CT-scan, bone marrow (BM) biopsy and peripheral blood (PB) and BM minimal residual disease (MRD) testing
• CR patients with uMRD received ibrutinib alone for 6 additional months, whereas others received 4 courses of fludarabine + cyclophosphamide and obinutuzumab while continuing ibrutinib
  • Patients with stable or progressive disease were taken off the study
• Primary objective was to obtain 30% of CR with uMRD in BM at 16 months
• Preliminary results of the induction phase of this trial, including toxicities and response rates were reported

Efficacy

• Seventy-three patients are evaluable so far for the response at M9. The ORR was 100% with 37% in CR (IWCLL criteria) and 63% in PR
• Among the 63 (86%) patients with positive BM MRD, 22 were in CR and 41 in PR; 8 patients had uMRD in PB and BM including 4 patients in CR
• These preliminary results indicated that this 9 month « chemo-free » induction is associated with a high CR rate (37%) without excess of toxicity
  • Majority of patients required subsequent immunochemotherapy because of detectable BM MRD

Safety

• Total of 37 serious AEs were observed with 24 related to the treatment, including 3 tumor lysis syndrome (grade 3), 5 cardiac events (1 hypertension (grade 3) and 2 atrial flutter (grade 2 and 3) and 2 atrial fibrillation (grade 3)), 1 diabetes mellitus (grade 2), 3 febrile neutropenia (grade 4), 2 neutropenia (grade 3), 1 pneumonia (grade 4), 1 hepatocellular injury (grade 3), 1 severe pain (grade 3), 1 hemoptysis (grade 3), 1 infection of listeria meningitis complicated with disseminated intravascular coagulation (grade 3), 1 thrombocytopenia (grade 4), 1 hemorrhagic renal cyst (grade 3), 1 brain hemorrhage (grade 4), 1 diarrhea ( grade 3) and 1 vomiting (grade 3)
• Among the other AE, Infusion Related Reaction (IRR) only occurred during Cycle 1 At Day 1 for 69,5% of the patients (34.8% grade 1, 57.6% grade 2 and 7.6% grade 3), 14.5% at Day 2 (only grade 1 and 2) and none at Day 8 and 15, respectively
• Grade 3-4 neutropenia were observed in 24.3%, 7.7%, 10.2%, 12.2%, 11.8%, 11,1%, 13.6%, 16.7% and 2.7% of cases during Cycles 1 to 9, respectively
• Grade 3-4 thrombocytopenia and anemia were mainly observed during cycle 1 (30.8% and 6%, respectively)
• Other significant toxicity was digestive (nausea, vomiting and diarrhea) occurring in 33.6% of the patients (grade 1 and 2) but only during Cycle 1

These data suggest this chemo-free induction strategy can produce a high CR rate (37%) without the challenge of unmanageable toxicity. It is also notable that the majority of the patients in this study required subsequent immunochemotherapy due to minimal residual disease detected in the bone marrow.